Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Saturated free fatty acid (FFA) is a major source of metabolic stress that activates the c-Jun NH(2)-terminal kinase (JNK). This FFA-stimulated JNK pathway is relevant to hallmarks of metabolic syndrome, including insulin resistance. Here we used gene ablation studies in mice to demonstrate a central role for mixed-lineage protein kinases (MLK) in this signaling pathway. Saturated FFA causes protein kinase C (PKC)-dependent activation of MLK3 that subsequently causes increased JNK activity by a mechanism that requires the MAP kinase kinases MKK4 and MKK7. Loss of PKC, MLK3, MKK4, or MKK7 expression prevents FFA-stimulated JNK activation. Together, these data establish a signaling pathway that mediates effects of metabolic stress on insulin resistance.
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PMID:Metabolic stress signaling mediated by mixed-lineage kinases. 1767 97

Kainate receptor containing GluR6 subunit (KAR) is involved in the neuronal cell death induced by cerebral ischemia/reperfusion (I/R). Hypothermia is an effective neuroprotectant in brain ischemia, whereas the neuroprotective mechanisms have not been clearly established. The present study was set out to examine whether hypothermia would cause the alternation of the assembly of the GluR6-PSD95-MLK3 signaling module and the activation of c-Jun N-terminal kinase (JNK) pathway through KAR. Hypothermia (32 degrees C) was induced 10 min before ischemia and was maintained for 3 h after ischemia. Our results indicated that hypothermia could inhibit the assembly of GluR6-PSD95-MLK3 signaling module and suppressed the activation of MLK3, MKK4/7, and JNK3. The inhibition of JNK3 activation by hypothermia diminished the phosphorylation of the transcription factor c-Jun and downregulated FasL expression in hippocampal CA1. Meanwhile, the inhibition of JNK3 activation by hypothermia attenuated bax translocation, the release of cytochrome c, and the activation of caspase-3 in CA1 subfields. Both GluR6 antagonist NS102 and GluR6 antisense oligodeoxynucleotides partly blocked the aforementioned effects of hypothermia, which was further confirmed by histology. Taken together, our results strongly suggest that hypothermia decreased the increased assembly of the GluR6-PSD95-MLK3 signaling module and the activation of JNK pathway induced by I/R through KAR, which gave a new insight into the ischemic therapy.
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PMID:Neuroprotection of hypothermia against neuronal death in rat hippocampus through inhibiting the increased assembly of GluR6-PSD95-MLK3 signaling module induced by cerebral ischemia/reperfusion. 1817 94

Mitogen-activated protein kinases (MAPKs) are key signaling molecules that respond to mitogenic stimulation or environmental stress, resulting in the expression of target proteins. c-Jun N-terminal kinase (JNK) and p38 MAPKs are activated by inflammatory cytokines or environmental stress. Specific p38 MAPK inhibitors, such as SB202190 or SB203580, are widely used to dissect p38 MAPK-related signal transduction mechanisms. While using SB202190 to inhibit p38 MAPK-related signaling, we observed that SB202190 treatment could activate JNK. Further experiments showed that treatment of cells with SB202190 could phosphorylate JNK and activating transcription factor 2 (ATF-2), and increased AP-1 DNA binding. Using multiple cell lines and primary endothelial cells, we demonstrated that specific p38 MAPK inhibitors SB202190 or SB203580 induces the activation of the JNK pathway. Further, using with RNA interference and kinase-inactive expression of intermediates of the JNK pathway, we demonstrated SB202190- or SB203580-induced JNK activation is dependent on the MLK-3-MKK4/MKK7-dependent signal transduction pathway. Finally, we demonstrate that treatment of cells with SB202190 or SB203580 induces the phosphorylation and activation of MLK3.
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PMID:Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7-dependent mechanism. 1822 47

In this study, we investigated whether the increase of inhibitory gamma-amino butyric acid (GABA) signal suppresses the excitatory glutamate signal induced by cerebral ischemia and the underlying mechanisms. In global cerebral ischemia, focal cerebral ischemia and oxygen-glucose deprivation, application of muscimol and baclofen, agonists of GABA(A) receptor and GABA(B) receptor, exerted neuroprotection. The agonists inhibited the increased assembly of the GluR6-PSD-95-MLK3 module induced by cerebral ischemia and the activation of the MLK3-MKK4/7-JNK3 cascade. Our results suggest that stimulation of the inhibitory GABA receptors can attenuate the excitatory JNK3 apoptotic signaling pathway via inhibiting the increased assembly of the GluR6-PSD-95-MLK3 signaling module in cerebral ischemia.
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PMID:Co-activation of GABA receptors inhibits the JNK3 apoptotic pathway via the disassembly of the GluR6-PSD95-MLK3 signaling module in cerebral ischemic-reperfusion. 1830 89

In this study, we investigated the role of hematopietic progenitor kinase 1 (HPK1) in delayed neuronal damage after cerebral ischemia and the possible regulatory mechanisms of this event. Our data show that tyrosine phosphorylation of HPK1 was significantly increased at 6 h of ischemic-reperfusion compared with sham control. The increase in p-HPK1, p-MLK3, p-MKK7, and p-JNK3 was attenuated by HPK1 antisense oligodeoxynucleotides intra-cerebroventricular infusion, but not MS-ODNs or vehicle. Intracerebroventricular infusion of antisense oligodeoxynucleotides also increased the number of surviving pyramidal neurons, whereas MS-ODNs or vehicle (TE) groups had no effects. These results indicate that knockdown of HPK1 expression provides neuroprotection through downregulation activation of the MLK3-MKK7-JNK3 pathway following cerebral ischemia in the rat hippocampus CA1 subfield.
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PMID:Neuroprotection against ischemic brain injury by knockdown of hematopietic progenitor kinase 1 expression. 1838 79

The mitogen-activated protein kinase kinase kinases of the mixed-lineage kinase (MLK) family have been shown to activate the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway, and to regulate the other two principal MAPK cascades, p38 and extracellular signal-regulated kinase (ERK). Although there is growing evidence for their involvement in neuronal cell death leading to neurodegenerative disorders, little in vivo data is available for the members of this family of kinases. Here, we report that the inactivation of mouse Mlk1 and Mlk2 genes. Mlk1(-/-) and Mlk2(-/-) mice were found to be viable and healthy. Surprisingly, mice carrying the compound Mlk1/Mlk2 null mutations were also found to be viable, fertile and to have a normal life span. The nervous system, testis and kidney, the major sites of MLK1 and 2 expression, all appear normal, as do other organs where these kinases were found to be more weakly expressed. Surprisingly, developmental neuronal programmed cell death, another potential target for MLK family members, was also found to be unaffected. Our results suggest that there is extensive functional redundancy between MLK1/MLK2 and the other member of the family, MLK3, which is also not required for survival in mouse.
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PMID:Mice lacking both mixed-lineage kinase genes Mlk1 and Mlk2 retain a wild type phenotype. 1841 56

Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 serine/threonine kinase super family. We recently reported that HPK1 is involved in c-Jun NH2-terminal kinase (JNK) signaling pathway by sequential activation of MLK3-MKK7-JNK3 after cerebral ischemia. Here, we used 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine (PP2) and MK801 to investigate the events upstream of HPK1 in ischemic brain injury. Immunoprecipitation and immunoblot results showed that PP2 and MK801 significantly decreased the activation of Src, HPK1, MLK3, JNK3 and c-Jun, respectively, during ischemia/reperfusion. Histology and TUNEL staining showed PP2 or MK801 protects against neuron death after brain ischemia. We speculate that this unique signaling pathway through the tyrosine phosphorylation of HPK1 promotes ischemic brain injury by activated Src via N-methyl-d-aspartate receptor and, ultimately, the activation of the MLK3-MKK7-JNK3 pathway after cerebral ischemia.
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PMID:Tyrosine phosphorylation of HPK1 by activated Src promotes ischemic brain injury in rat hippocampal CA1 region. 1849 70

Our previous study showed that kainate (KA) receptor subunit GluR6 played an important role in ischemia-induced MLK3 and JNK activation and neuronal degeneration through the GluR6-PSD95-MLK3 signaling module. However, whether the KA receptors subunit GluR6 is involved in the activation of p38 MAP kinase during the transient brain ischemia/reperfusion (I/R) in the rat hippocampal CA1 subfield is still unknown. In this present study, we first evaluated the time-course of phospho-p38 MAP kinase at various time-points after 15 min of ischemia and then observed the effects of antagonist of KA receptor subunit GluR6, GluR6 antisence oligodeoxynucleotides on the phosphorylation of p38 MAP kinase induced by I/R. Results showed that inhibiting KA receptor GluR6 or suppressing the expression of KA receptor GluR6 could down-regulate the elevation of phospho-p38 MAP kinase induced by I/R. These drugs also reduced the phosphorylation of MLK3, MKK3/MKK6, MKK4, and MAPKAPK2. Additionally, our results indicated administration of three drugs, including p38 MAP kinase inhibitor before brain ischemia significantly decreased the number of TUNEL-positive cells detected at 3 days of reperfusion and increased the number of the surviving CA1 pyramidal cells at 5 days of reperfusion after 15 min of ischemia. Taken together, we suggest that GluR6-contained KA receptors can mediate p38 MAP kinase activation through a kinase cascade, including MLK3, MKK3/MKK6, and MKK4 and then induce increased phosphorylation of MAPKAPK-2 during ischemia injury and ultimately result in neuronal cell death in the rat hippocampal CA1 region.
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PMID:GluR6-containing KA receptor mediates the activation of p38 MAP kinase in rat hippocampal CA1 region during brain ischemia injury. 1868 Jan 60

Amyloid-beta peptide (Abeta) has been implicated in the etiopathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms underlying Abeta neurotoxicity remain to be elucidated. This study showed that Abeta treatment resulted in the increased phosphorylation (activation) of MLK3, MKK7, and JNK3 in cultured cortical neurons, which characterized as biphasic activation (first peaked at 1 hr and second peaked at 12 hr after Abeta treatment). K252a blocked Abeta-induced neuronal apoptosis, both early and late phases of MLK3-MKK7-JNK3 activation, as well as downstream signal events involving p-JNKs nuclear translocation, c-Jun phosphorylation, and Bad translocation to the mitochondria. The neuroprotective effect of K252a on Abeta-induced apoptosis was partially dependent on Akt activation. In contrast, antioxidant N-acetyl-L-cysteine (NAC) reduced early, but not late, MLK3-MKK7-JNK3 activation by Abeta treatment and provided a weak neuroprotective ability in Abeta-induced apoptosis. Taken together, Abeta neurotoxicity is mainly due to MLK3-MKK7-JNK3 signal cascades. The late signal events of MLK3 activation after Abeta treatment may play an important role in AD neuronal loss and will be a promising pharmacological target for AD therapeutic intervention.
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PMID:Different protection of K252a and N-acetyl-L-cysteine against amyloid-beta peptide-induced cortical neuron apoptosis involving inhibition of MLK3-MKK7-JNK3 signal cascades. 1895 97

Previous studies have shown that KA receptor subunit GluR6 mediated c-Jun N-terminal protein kinase (JNK) signaling is involved in global ischemia injury. Our present study indicates that focal ischemic brain insult on rat middle cerebral artery occlusion (MACo) model enhances the assembly of the GluR6-PSD95-MLK3 module and facilitates the phosphorylation of JNK. Most importantly, a peptide containing the TAT protein transduction sequence, Tat-GluR6-9c, can perturb the assembly of the GluR6-PSD95-MLK3 signaling module and suppress the activation of MLK3, MKK7/4 and JNK. As result, the inhibition of JNK activation caused by Tat-GluR6-9c diminishes the phosphorylation of the transcription factor c-Jun, down-regulates FasL expression and attenuates bax translocation, release of cytochrome c and the activation of caspase-3. Furthermore, MCAo induced infract volume is reduced by intracerebroventricular injection of Tat-Glur6-9c. Oxygen-glucose-deprivation (OGD) cultured cortical neuronal cell also shows an improved cell viability by application of Tat-GluR6-9c. Taken together, our findings strongly suggest that GluR6-PSD95-MLK3 signaling module mediated activation of nuclear and non-nuclear pathways of JNK activation are involved in focal ischemia injury and OGD. Tat-GluR6-9c, the peptide we constructed, gives a new insight into the therapy for ischemic stroke.
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PMID:Neuroprotection against transient focal cerebral ischemia and oxygen-glucose deprivation by interference with GluR6-PSD95 protein interaction. 1944 6


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